Aoki Tomohiro, Kataoka Hiroharu, Ishibashi Ryota, Nozaki Kazuhiko, Hashimoto Nobuo
Department of Neurosurgery, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Stroke. 2008 Sep;39(9):2603-10. doi: 10.1161/STROKEAHA.107.513648. Epub 2008 Jul 17.
A cerebral aneurysm (CA) causes catastrophic subarachnoid hemorrhage. Degradation of extracellular matrix in arterial walls is a prominent feature of cerebral aneurysms. We investigated the expression and role of cysteine cathepsins, collagen- and elastin- degrading proteinases, in CA progression.
CAs were induced in Sprague-Dawley rats with or without cysteine cathepsin inhibitor, NC-2300. Expression of cathepsin B, K, S, and cystatin C, an endogenous inhibitor of cysteine cathepsins, in aneurysmal walls was examined in quantitative RT-PCR and immunohistochemistry. The activity of cysteine cathepsins and collagenase I and IV in aneurysmal walls was also assessed. Finally, expression of cysteine cathepsins and cystatin C in human CAs was examined.
Quantitative RT-PCR and immunohistochemistry revealed upregulated expression of cathepsin B, K, and S in the late stage of aneurysm progression. In contrast, cystatin C expression was reduced with aneurysm progression. Treatment with NC-2300 resulted in the decreased incidence of advanced CAs. The activity of cysteine cathepsins and collagenase I and IV in aneurysmal walls was reduced and elastin content was increased in the NC-2300-treated group. Finally, immunohistochemistry for cysteine cathepsins and cystatin C expression in human CAs showed the same expression pattern as in the rat study.
Data obtained by using NC-2300 revealed an important role of cysteine cathepsins in the progression of CAs. Our findings strongly suggest that an imbalance between cysteine cathepsins and their inhibitor may cause the excessive breakdown of extracellular matrix in the arterial walls leading to the progression and rupture of CAs.
脑动脉瘤（CA）可引发灾难性的蛛网膜下腔出血。动脉壁细胞外基质的降解是脑动脉瘤的一个显著特征。我们研究了半胱氨酸组织蛋白酶（胶原蛋白和弹性蛋白降解蛋白酶）在脑动脉瘤进展中的表达及作用。
在有或没有半胱氨酸组织蛋白酶抑制剂NC - 2300的情况下，诱导斯普拉格 - 道利大鼠形成脑动脉瘤。通过定量逆转录聚合酶链反应（RT - PCR）和免疫组织化学检测动脉瘤壁中组织蛋白酶B、K、S以及半胱氨酸组织蛋白酶的内源性抑制剂胱抑素C的表达。还评估了动脉瘤壁中半胱氨酸组织蛋白酶以及胶原酶I和IV的活性。最后，检测了人脑动脉瘤中半胱氨酸组织蛋白酶和胱抑素C的表达。
定量RT - PCR和免疫组织化学显示，在动脉瘤进展后期，组织蛋白酶B、K和S的表达上调。相反，随着动脉瘤进展，胱抑素C的表达降低。用NC - 2300治疗导致晚期脑动脉瘤的发生率降低。在NC - 2300治疗组中，动脉瘤壁中半胱氨酸组织蛋白酶以及胶原酶I和IV的活性降低，弹性蛋白含量增加。最后，人脑动脉瘤中半胱氨酸组织蛋白酶和胱抑素C表达的免疫组织化学显示与大鼠研究中的表达模式相同。
使用NC - 2300获得的数据揭示了半胱氨酸组织蛋白酶在脑动脉瘤进展中的重要作用。我们的研究结果强烈表明，半胱氨酸组织蛋白酶与其抑制剂之间的失衡可能导致动脉壁细胞外基质过度分解，从而导致脑动脉瘤的进展和破裂。
